Nerve growth factor (NGF) is a secreted protein that was discovered over 50 years ago as a molecule that promotes the survival and differentiation of sensory and sympathetic neurons. (See Levi-Montalcini, Science 187: 113 (1975), for a review). The crystal structure of NGF and NGF in complex with the tyrosinekinase A (TrkA) receptor has been determined (McDonald et al., Nature 354: 411 (1991); Wiesmann et al., Nature 401: 184-188 (1999)).
The role of NGF in the development and survival of both peripheral and central neurons has been well characterized. NGF has been shown to be a critical survival and maintenance factor in the development of peripheral sympathetic and embryonic sensory neurons and of basal forebrain cholinergic neurons (see, e.g., Smeyne et al., Nature 368: 246-9 (1994); and Crowley et al., Cell, 76:1001-11 (1994)). It has been shown to inhibit amyloidogenesis that leads to Alzheimer's disease (Calissano et al., Cell Death and Differentiation, 17: 1126-1133 (2010)). NGF up-regulates expression of neuropeptides in sensory neurons (Lindsay et al., Nature, 337:362-364 (1989)) and its activity is mediated through two different membrane-bound receptors, the TrkA receptor and the p75 common neurotrophin receptor (Chao et al., Science, 232:518-521 (1986); Huang et al., Annu. Rev. Neurosci., 24:677-736 (2001); Bibel et al., Genes Dev., 14:2919-2937 (2000)).
NGF is produced by a number of cell types including mast cells (Leon, et al., Proc. Natl. Acad. Sci., 91: 3739-3743 (1994)), B-lymphocytes (Torcia, et al., Cell, 85: 345-356 (1996), keratinocytes (Di Marco, et al., J. Biol. Chem., 268: 22838-22846)), smooth muscle cells (Ueyama, et al., J. Hypertens., 11: 1061-1065 (1993)), fibroblasts (Lindholm, et al., Eur. J. Neurosci., 2: 795-801 (1990)), bronchial epithelial cells (Kassel, et al., Clin, Exp. Allergy, 31:1432-40 (2001)), renal mesangial cells (Steiner, et al., Am. J. Physiol., 261:F792-798 (1991)) and skeletal muscle myotubes (Schwartz, et al., J. Photochem. Photobiol., B66: 195-200 (2002)). In addition, NGF receptors have been found on a variety of cell types outside of the nervous system.
NGF has been implicated in processes outside of the nervous system, e.g., NGF has been shown to enhance vascular permeability (Otten, et al., Eur J. Pharmacol., 106: 199-201 (1984)), enhance T- and B-cell immune responses (Otten, et al., Proc. Natl. Acad. Sci., USA 86: 10059-10063 (1989)), induce lymphocyte differentiation and mast cell proliferation and cause the release of soluble biological signals from mast cells (Matsuda, et al., Proc. Natl. Acad. Sci., 85: 6508-6512 (1988); Pearce, et al., J. Physiol., 372:379-393 (1986); Bischoff, et al., Blood, 79: 2662-2669 (1992); Horigome, et al., J. Biol. Chem., 268: 14881-14887 (1993)).
Both local and systemic administrations of NGF have been shown to elicit hyperalgesia and allodynia (Lewin, G. R. et al., Eur. J. Neurosci. 6: 1903-1912 (1994)). Intravenous infusion of NGF in humans produces a whole body myalgia while local administration evokes injection site hyperalgesia and allodynia in addition to the systemic effects (Apfel, S. C. et al., Neurology, 51: 695-702 (1998)). Furthermore, in certain forms of cancer, excess NGF facilitates the growth and infiltration of nerve fibers with induction of cancer pain (Zhu, Z. et al., J. Clin. Oncol., 17: 241-228 (1999)). Although exogenously added NGF has been shown to be capable of having all of these effects, it is important to note that it has only rarely been shown that endogenous NGF is important in any of these processes in vivo (Torcia, et al., Cell, 85(3): 345-56 (1996)).
An elevated level of NGF has been implicated in certain inflammatory conditions in humans and animals, e.g., systemic lupus erythematosus (Bracci-Laudiero, et al., Neuroreport, 4: 563-565 (1993)), multiple sclerosis (Bracci-Laudiero, et al., Neurosci. Lett., 147:9-12 (1992)), psoriasis (Raychaudhuri, et al., Acta Derm. l'enereol., 78: 84-86 (1998)), arthritis (Falcim, et al., Ann. Rheum. Dis., 55: 745-748 (1996)), interstitial cystitis (Okragly, et al., J. Urology, 161: 438-441 (1999)) and asthma (Braun, et al., Eur. J. Immunol., 28:3240-3251 (1998)). The synovium of patients affected by rheumatoid arthritis expresses high levels of NGF while in non-inflamed synovium NGF has been reported to be undetectable (Aloe, et al., Arch. Rheum., 35:351-355 (1992)). Similar results were seen in rats with experimentally induced rheumatoid arthritis (Aloe, et al., Clin. Exp. Rheumatol., 10: 203-204 (1992)). Elevated levels of NGF have been reported in transgenic arthritic mice along with an increase in the number of mast cells (Aloe, et al., Int. J. Tissue Reactions-Exp. Clin. Aspects, 15: 139-143 (1993)). Additionally, elevated levels of expression of canine NGF has been shown in lame dogs (Isola, M., Ferrari, V., Stabile, F., Bernardini, D., Canner, P., Busetto, R. Nerve growth factor concentrations in the synovial fluid from healthy dogs and dogs with secondary osteoarthritis. Vet. Comp. Orthop. Traumatol. 4: 279 (2011)). PCT Publication No. WO 02/096458 discloses use of anti-NGF antibodies of certain properties in treating various NGF related disorders such as inflammatory condition (e.g., rheumatoid arthritis). It has been reported that a purified anti-NGF antibody injected into arthritic transgenic mice carrying the human tumor necrosis factor (TNF) gene caused reduction in the number of mast cells, as well as a decrease in histamine and substance P levels within the synovium of arthritis mice (Aloe et al., Rheumatol. Int., 14: 249-252 (1995)). It has been shown that exogenous administration of a NGF antibody reduced the enhanced level of TNF occurring in arthritic mice (Manni et al., Rheumatol. Int., 18: 97-102 (1998)).
Increased expression of NGF and high affinity NGF receptor (TrkA) was observed in human osteoarthritis chondrocytes (Iannone et al., Rheumatology, 41: 1413-1418 (2002)). Rodent anti-NGF antagonist antibodies have been reported (Hongo et al., Hybridoma, 19(3):215-227 (2000); Ruberti et al., Cell. Molec. Neurobiol., 13(5): 559-568 (1993)). However, when rodent antibodies are used therapeutically in non-rodent subjects, an anti-murine antibody response develops in significant numbers of treated subjects.
The involvement of NGF in chronic pain has led to considerable interest in therapeutic approaches based on inhibiting the effects of NGF (Saragovi, et al., Trends Pharmacol Sci. 21: 93-98 (2000)). For example, a soluble form of the TrkA receptor was used to block the activity of NGF, which was shown to significantly reduce the formation of neuromas, responsible for neuropathic pain, without damaging the cell bodies of the lesioned neurons (Kryger, et al., J. Hand Surg. (Am.), 26: 635-644 (2001)).
Certain anti-NGF antibodies have been described (PCT Publication Nos. WO 2001/78698, WO 2001/64247, WO 2002/096458, WO 2004/032870, WO 2005/061540, WO 2006/131951, WO 2006/110883; U.S. Publication Nos. US 20050074821, US 20080033157, US 20080182978 and US 20090041717; and U.S. Pat. No. 7,449,616). In animal models of neuropathic pain (e.g., nerve trunk or spinal nerve ligation) systemic injection of neutralizing antibodies to NGF prevents both allodynia and hyperalgesia (Ramer et al., Eur. J. Neurosci., 11: 837-846 (1999); Ro et al., Pain, 79: 265-274 (1999)). Furthermore, treatment with a neutralizing anti-NGF antibody produces significant pain reduction in a murine cancer pain model (Sevcik et al., Pain, 115: 128-141 (2005)). Thus, there is a serious need for anti-NGF antagonist antibodies for humans and animals.